Abstract
The BAL1 macrodomain-containing protein and its partner E3 ligase, BBAP, are overexpressed in chemotherapy-resistant lymphomas. BBAP selectively ubiquitylates histone H4 and indirectly promotes early 53BP1 recruitment to DNA damage sites. However, neither BBAP nor BAL1 has been directly associated with a DNA damage response (DDR), and the function of BAL1 remains undefined. Herein, we describe a direct link between rapid and short-lived poly(ADP-ribose) (PAR) polymerase 1 (PARP1) activation and PARylation at DNA damage sites, PAR-dependent recruitment of the BAL1 macrodomain-containing protein and its partner E3 ligase, local BBAP-mediated ubiquitylation, and subsequent recruitment of the checkpoint mediators 53BP1 and BRCA1. The PARP1-dependent localization of BAL1-BBAP functionally limits both early and delayed DNA damage and enhances cellular viability independent of ATM, MDC1, and RNF8. These data establish that BAL1 and BBAP are bona fide members of a DNA damage response pathway and are directly associated with PARP1 activation, BRCA1 recruitment, and double-strand break repair.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Ataxia Telangiectasia Mutated Proteins
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Carrier Proteins / analysis
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Carrier Proteins / metabolism
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Cell Cycle Proteins / analysis
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Cell Cycle Proteins / metabolism*
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Cell Line
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DNA Breaks, Double-Stranded*
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DNA Repair
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / metabolism*
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Histone Chaperones
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Humans
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Neoplasm Proteins / analysis
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / analysis
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Nuclear Proteins / metabolism*
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Poly (ADP-Ribose) Polymerase-1
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Poly Adenosine Diphosphate Ribose / analysis
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Poly Adenosine Diphosphate Ribose / metabolism*
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Poly(ADP-ribose) Polymerases / analysis
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Poly(ADP-ribose) Polymerases / metabolism
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Protein Serine-Threonine Kinases / analysis
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Trans-Activators / analysis
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Trans-Activators / metabolism*
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Tumor Suppressor Proteins / analysis
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin-Protein Ligases / analysis
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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Histone Chaperones
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MDC1 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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PARP9 protein, human
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RNF8 protein, human
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Trans-Activators
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Tumor Suppressor Proteins
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UIMC1 protein, human
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Poly Adenosine Diphosphate Ribose
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DTX3L protein, human
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Ubiquitin-Protein Ligases
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases